Abstract
Pathogenic bacterial infections of the lung are life threatening and underpin chronic lung diseases. Current treatments are often ineffective potentially due to increasing antibiotic resistance and impairment of innate immunity by disease processes and steroid therapy. Manipulation miRNA directly regulating anti-microbial machinery of the innate immune system may boost host defence responses. Here we demonstrate that miR-328 is a key element of the host response to pulmonary infection with non-typeable haemophilus influenzae and pharmacological inhibition in mouse and human macrophages augments phagocytosis, the production of reactive oxygen species, and microbicidal activity. Moreover, inhibition of miR-328 in respiratory models of infection, steroid-induced immunosuppression, and smoke-induced emphysema enhances bacterial clearance. Thus, miRNA pathways can be targeted in the lung to enhance host defence against a clinically relevant microbial infection and offer a potential new anti-microbial approach for the treatment of respiratory diseases.
Highlights
Pathogenic bacterial infections of the respiratory tract are major causes of morbidity, are difficult to treat and can be life-threatening [1]
MiRNAs have been identified as important regulators of gene expression programs, which regulate differentiation, growth and function of innate and adaptive immune cells
Using miRNA microarray, we demonstrated that lung miRNAs were differentially expressed following non-typeable Haemophilus Influenzae (NTHi) infection in mice
Summary
Pathogenic bacterial infections of the respiratory tract are major causes of morbidity, are difficult to treat and can be life-threatening [1] They play a critical role in the pathogenesis of many inflammatory conditions of the lung (e.g. chronic obstructive pulmonary disease (COPD) and cystic fibrosis) and are major causes of acute exacerbations of pre-existing disease [2,3,4]. Important roles for microRNA (miRNA) in regulating innate host defence responses and acquired immunity have been identified [10,11]. Key examples of miRNAs that are known to be activated by pathogen associated molecular patterns (PAMPs) include miR-9 [13], miR-146 [14] and miR-155 [14], which are important in regulating inflammatory pathways in macrophages and neutrophils by controlling TLR signaling. Recent studies have demonstrated that miRNAs such as miR155 [15,16], miR-21 [17], and miR-29 [18] are involved in regulating bacterial infections through the innate immune system
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